Analgetic compositions

ABSTRACT

A NEW AND NOVEL ORALLY EFFECTIVE, ANALGESTIC COMPOSITION HAS BEEN FOUND WHICH, UPON PARENTERAL ADMINISTRATION, DOES NOT PRODUCE ANALGESIA, EUPHORIA OR PHYSICAL DEPENDENCE, SAID COMPOSITION COMPRISING AN ORALLY INACTIVE DOSE OF NALOXONE AND AN ORALLY ACTIVE, STRONG ANALGETIC IN ORAL DOSAGE FORM AND CONTAINING FOR EACH ANALGETIC DOES OF THE ANALGETIC AGENT AN AMOUNT OF NALOXONE SUFFICIENT, UPON PARENTERAL ADMINISTRATION OF SAID ORAL DOSAGE FORM, TO NEGATE THE ANALGETIC, EUPHORETIC AND DEPENDENCE PRODUCING ACTION OF THE COMPOSITION. TWO PREFERRED COMPOSITIONS WOULD BE: (1) 1.0 MG. OF NALOXONE AND 2.5 MG. OF PHENAZOCINE; (2) 1.0 MG. OF NALOXONE AND 5 MG. OF METHADONE.

United States Patent ()flice 3,773,955 Patented Nov. 20, 1973 3,773,955ANALGETIC COMPOSITIONS Irwin Jacob Pachter, Woodbury, N.Y., and MaxwellGordon, Philadelphia, Pa., assignors to Bristol-Myers Company, New York,N.Y.

No Drawing. Filed Aug. 3, 1970, Ser. No. 60,621 Int. Cl. A61k 27/00 US.Cl. 424-260 3 Claims ABSTRACT OF THE DISCLOSURE A new and novel orallyeffective, analgetic composition has been found which, upon parenteraladministration, does not produce analgesia, euphoria or physicaldependence, said composition comprising an orally inactive dose ofnaloxone and an orally active, strong analgetic in oral dosage form andcontaining for each analgetic dose of the analgetic agent an amount ofnaloxone sufficient, upon parenteral administration of said oral dosageform, to negate the analgetic, euphoretic and dependence producingaction of the composition.

'IWvo preferred compositions would be: (1) 1.0 mg. of naloxone and 2.5mg. of phenazocine; (2) 1.0 mg. of naloxone and 5 mg. of methadone.

BACKGROUND OF THE INVENTION (1) Field of the invention This invention isin the field of combinations of drug for medicinal purposes, inparticular, analgetic compositions for the treatment of pain.

(2) Description of the prior art (A) US. Pat. No. 3,254,088 which issuedMay 31, 1966, describes the preparation of naloxone and its activity asa narcotic antagonist.

(B) US. Pat. No. 3,493,657 which issued Feb. 3, 1970, describes thecombination of morphine and naloxone as a composition for parenteral usewhich has a strong analgetic, as well as antagonistic effect, withoutthe occurrence of undesired or dangerous side effects.

(C) A New York Times article appearing in a July 14, 1970 issuedescribes the oral administration of naloxone to narcotic addicts as amethod of treatment. The oral administration of naloxone (in high doses)makes it impossible for the addict to experience a high no matter howmuch heroin he uses.

Applicants are of the opinion that the prior art neither teaches norsuggests the compositions of the instant invention, said compositionsbeing orally active analgetic agent producing neither analgesia,euphoria or physical dependence upon parenteral administration.

Drug abuse has almost become a way of life to a rapidly growing segmentof the world population, especially here in the United States. It hasbecome the vogue of many of the younger generation, to experiment withany type of drug that will produce an emotional, psychological,euphoric, depressive or generally psychodelic experience.

Those drugs most commonly employed for such illicit purposes include thebarbiturates, lysergic acid, diethylamide (LSD), mescaline, marijuana(tetrahydrocannabinol), strong analgetics (heroin, codeine, morphine,meperidine, propoxyphene [Darvon], methadone, dihydrocodeinone,pentazocine, and the like), the central nervous system stimulants (theamphetamines and the like) and some of the major and minor tranquilizers(the promazines, meprobamate, the diazepines, and the like). Most ofthese compounds are commonly used in medicine for the legitimatetreatment of various conditions and therefore have a limitedavailability in our society. .While these agents are a necessary part ofmodern medicine, it would be highly desirable (1) to produce new drugsthat do not possess drug abuse potential or (2) to denature the oldagents to prevent their illicit use. The pharmaceutical industry hasbeen striving to achieve the first goal for many years but mostregretably has only achieved very moderate success. If one focuses onthe strong analgetics, it becomes apparent that much effort and moneyhas been expended to produce chemicals possessing good analgeticactivity but little or no addictive liability. While good progress hasbeen made as evidenced, for example, by the development of propoxypheneas a replacement for codeine and pentazocine as a replacement formorphine or meperidine, it is unfortunate that these compounds are stillreported in the medical literature to be addictive and/or euphoric andsubjected to abuse by parenteral administration. Furthermore, some ofthese agents have undesirable side effects, i.e., bad hallucinations,etc.

It is commonly known to the narcotic enforcement agencies and others inthe medical trades that a substantially large amount of the stronganalgetics destined for legitimate medicinal use become diverted bydishonest or careless handling. In most instances these compounds areobtained by the addict or potential addict by theft or casualprescribing practice by the physician.

It is known from experience that the true narcotic addict must feed hishabit by the parenteral route (mainlining) to obtain the maximumeuphoric elfect. The potential addict or thrill-seeker will alsoexperiment in the same manner. Unfortunately, a substantial amount ofthe legitimate strong analgetics formulated in oral dosage form arediverted to parenteral use and abuse. Since the oral dosage forms ofthese drugs diverted from legitimate channels must be parenterallyusable to produce the desired euphoria, it follows that if these oraldosage forms are in some way rendered inactive or unpleasant forparenteral use the addict or potential addict will be out oif from thisparticular supply of euphoretic drugs.

Naloxone, chemically known as l-N-allyl 14 hydroxynordihydromorphinone(Merck Index, 8th ed., p. 712, Merck & Co., Rahway, N.J.; US. Pat. No.3,254,088 [1966]), is a potent narcotic antagonist when administeredparenterally. The parenteral product is useful for the treatment ofnarcotic overdosage or for the detection of addiction. However, whilenaloxone is extremely potent parenterally (a parenteral dose of 0.1 mg.to 2.5 mg.

will produce narcotic withdrawal symptoms in the addict or have anarcotic reversal effect in an overdose situation), the compound must beadministered in quantities 200 to 400 times greater than the parenteraldose to obtain the same effect orally. It is known that thecontemporaneous parenteral administration of equivalent therapeuticdoses of naloxone and an euphoretic narcotic or narcotic-like analgeticwill negate the analgetic and euphoretic elfect in the normal-individualand the euphoric and/or maintenance effect of the analgetic in theaddict.

Many interchangeable terms are commonly used to describe the psychic orphysical dependence of people upon drugs. The term addiction is mostcommonly used when talking about the strong analgetics. The stronganalgetics, in contrast to the weaker agents such as aspirin,acetaminophen, and the like, are employed in the relief of more severepain. They usually produce a euphoric efiect on parenteraladministration.

Addiction can develop to the barbiturates and strong analgetic agents,in the sense of the term addiction as defined by the Committee onProblems of Drug Dependence of the National Research Council, formerlyknown as the Drug Addiction Committee of The National Research Council,namely, a state of periodic or chronic intoxication, detrimental to theindividual and to society, produced by the repeated administration of adrug, its

characteristics are a compulsion to take the drug and to increase thedose, with the development of phychic and sometimes physical dependenceon the effects of the drug, so that the development of means to continuethe administration of the drug becomes an important motive in theaddicts existence.

Addiction to the strong narcotic or narcotic-like analgetics oftenoccurs by the legitimate chronic parenteral administration of theseagents in the alleviation of deep pain. More commonly, however,addiction to these agents occurs when the psychologically unbalanced orthrillseeking individual looking for an escape from the realities oflife finds his escape in the euphoria produced by the parenteraladministration of strong analgetics. Euphoria .is generally defined as afeeling of well-being. Euphoria can be produced in many ways, e.g., anexhilarating experience, alcohol, stimulants, depressants, narcotics,etc. For the purpose of this disclosure, euphoria is defined as anabnormal state of well-being produced by the parenteral administrationof strong analgetic agents. The terms euphoretic analgetics and stronganalgetics, often called narcotic or narcotic-like analgetics, are alsodefined herein as including those chemical agents which upon parenteraladministration are capable of maintaining or partially maintaining aknown addict addicted to heroin or the like without substantialwithdrawal symptoms. For the purpose of this disclosure, a stronganalgetic is also defined herein as any analgetic agent Whose analgetic,euphoric or dependence producing actions are negated by the parenteraladministration of naloxone or a salt thereof.

SUMMARY OF THE INVENTION It was an object of this invention to develop apotent, orally efiective, but parenterally inactive analgeticcomposition that would have essentially no drug abuse potential. Theobject of the invention was achieved by the formulation of a compositioncomprising an orally inactive dose of naloxone and an orally activestrong, i.e., narcotic or narcotic-like, analgetic agent in oral dosageform which, when administered parenterally, had no drug abuse potential.

It is our invention to combine a parenterally effective but orallyineflective dose of naloxone with an oral analgetic dose of an orallyeffective strong analgetic without interfering with the analgetic effectof the analgetic upon oral administration. At the same time, however, ifany of the oral dosage form should be diverted into the hands of theaddict or potential addict, the composition when injected parenterallywould not produce any euphoria and in an addict would, in fact, actuallycause some withdrawal symptoms.

Examples of some representative orally active strong analgetics andtheir preferred oral dosage ranges are: meperidine (SO-250 mg.),oxymorphone (-25 mg.), alphaprodine (50-250 mg.), anileridine (25-150mg.), dextromoramide (5-25 mg.), dextropropoxyphene (32- 150 mg.),methadone (5-25 mg.), metopon (3-15 mg.), levorpanol (2-10 mg.),phenazocine (2-10 mg.), etoheptazine (100-500 mg.), propiram (50-500mg.), profadol (-250 mg.), phenampromide (50-250 mg.), thiambutene(20-150 mg.), pentazocine (20-200 mg.), pholcodeine (-250 mg.), codeine(15-150 mg.), oxycodone (5-50 mg.), dihydrocodeinone (5-100 mg.),hydromorphone (IO-100 mg.), fentanyl (0.5-10 mg.), 3-transdimethylamino4 phenyl 4 trans-carbethoxy-A-cyclohexene (-250 mg.),3-dimethylamino-O-(4 methoxyphenylcarbamoyl) propiophenone oxime (25-150mg.), (----)}3 2 hydroxy 2,9 dimethyl 5 phenyl- 6,7 benzomorphan (10-150mg.), ()2' hydroxy 2 (3 methyl 2 butenyl) 9 methyl 5 phenyl 6,7-benzomorphan (20-300 mg.), pirinitramide (10-150 mg.), (-)a 5,9 diethyl2' hydroxy 2 methyl- 6,7 benzomorphan (50-250 mg.), ethylI-(Z-dimethylaminoethyl) 4,5,6,7 tetrahydro 3 methyl 4 0x0- 6phenylindole 2 carboxylate (SO- mg.), l-benzoylmethyl 2,3 dimethyl 3(m-hydroxyphenyl)- piperidine (50-500 mg.), N-allyl 7a (l-(R) hydroxy- 1methylb-utyl) 6,14 endo ethenotetrahydronororipavine (50-250 mg.), (-)2hydroxy 2 methyl 6,7- benzomorphan (50-250 mg.), noracylmetadol (10-150mg.), phenoperidine (5-100 mg.), or dl methadol (5- 25 mg.), ,3 dlmethadol (35-250 mg.), a l methadol (2-15 mg.), 13 dl -acetylmethadol(1-10 mg.), oc-lacetylmethadol (l-l0 mg.) and fl-l-acetylmethadol (2- 25mg.).

When the term naloxone or the name of a strong analgetic agent is usedherein, it is to be understood that any and all the pharmaceuticallyacceptable nontoxic salts thereof are also an integral part of thisinvention. The salts of these agents would include amongst others, thehydrochlorides, sulfates, bisulfates, tartrates, nitrates, ci-trates,bitartrates, phosphates, malates, maleates, hydrobromides, hydroiodides,fumarates, succinates, and the like.

The compositions of the present invention can be formulated into any ofthe known pharmaceutical forms for oral administration. As such the termoral dosage form includes solid compositions for oral administration inunit dosage form such as tablets, capsules, granules, powders, cachetsor the like. Bulk powders of fixed composition for subdivision intotherapeutic quantities, solutions, emulsions or suspensions of thecomposition are also included in the definition.

The compositions of the instant invention can also contain other activeingredients. These include amongst others for example, aspirin,phenacetin, caffeine, acetaminophen, antihistamines, homatropinemethylbromide, phenyltoloxamine citrate, barbiturates, or the like, ormultiple combinations thereof. Also included within the scope of thepresent invention are those compositions compriing naloxone incombination with those antitussive preparations which contain narcoticor narcotic-like cough suppressants such as codeine, dihydrocodeinone,pholcodeine, and the like. Other products comprising a narcotic ornarcoticlike composition for use as an antispasmotic in thegastrointestinal tract, such as Camphorated Opium Tincture, U.S.P.,Opium Tincture, U.S.P., Opium Extract, N.F., and the like can also bedenatured with naloxone and they are also considered an integral part ofthis invention.

One especially valued composition of the present invention is the orallyactive combination of methadone and naloxone. This is particularly sobecause of the recently acknowledged and accepted method of treatingformer narcotic addicts with methadone. The regimen of treatmentinvolves the oral dosing of the addict one or more times a day with amaintenance dose of methadone adequate to prevent narcotic craving. Onemajor disadvantage of the program is the necessity of the former addictto report to a treatment center one or more times a day .to receive hismethadone. The oral methadone must be administered in the presence of ahealth officer to prevent its diversion into illicit channels where itcan be abused parenterally so as to obtain a euphoric effect. However,this would not be so if the composition of the instant invention were tobe employed. As explained above, the naloxone-methadone compositionwould be orally active but could not be diverted to parenteral usebecause of the presence of the narcotic antagonist, naloxone. It wouldtherefore be possible to supply an addict with several days supply ofhis maintenance dose of methadone Without fear of the composition beingused for other than that intended.

A preferred embodiment of the present invention is an orally effective,analgetic composition which, upon parenteral administration, does notproduce analgesia, euphoria or physical dependence, said CompositionCompris- 7 ing an orally ineffective but parenterally effective dose ofnaloxone and an orally active, strong analgetic in oral dosage form.

A preferred embodiment of the present invention is an orally effective,analgetic composition which, upon parenteral administration does notproduce analgesia, euphoria or physical dependence, said compositioncomprising an orally ineffective but parenterally effective dose ofnaloxone and an analgetic dose of an orally active, strong analgetic inoral dosage form.

Another preferred embodiment is an orally effective, analgeticcomposition which, upon parenteral administration does not produceanalgesia, euphoria or physical dependence, said composition comprisingnaloxone and an orally active, strong analgetic in oral dosage form andcontaining for each analgetic dose of the analgetic agent an amount ofnaloxone sufficient upon parenteral administration of said oral dosageform to negate the analgetic and euphoric action of the composition.

A more preferred embodiment is an orally effective, analgeticcomposition which, upon parenteral administration, does not produceanalgesia, euphoria or physical dependence, said composition comprisingnaloxone and an analgetic selected from the group consisting ofmeperidine, oxymorphone, alphaprodine, anileridine, dextromoramide,dextropropoxyphene, methadone, metopon, levorphanol, phenazocine,etoheptazine, propiram, profadol, phenampromide, thiambutene,pentazocine, pholcodeine, codeine, oxycodone, dihydrocodeinone,hydromorphone, fentanyl,

3 trans dimethylamino 4 phenyl-4-trans-carbethoxy- A cyclohexene, 3dimethylamino-Q-(4-methoxyphenylcarbamoyl)-propiophenone oxime, 18 2'hydroxy- 2,9 dimethyl 5 phenyl 6,7-benzomorphan, (-)2- hydroxy 2 (3methyl Z-butenyl)-9 methyl-5-phenyl- 6,7-benzomorphan, pirinitramide,)-a-5,9-diethyl-2'- hydroxy-2-methyl-6,7-benzomorphan, ethyl1-(2-dimethylamioethyl) 4,5,6,7 tetrahydro 3 methyl-4-oxo-6-phenylindole 2 carboxylate, 1 benzoylmethyl-2,3-dimethyl 3 (mhydroxyphenyl)-piperidine, N-allyl-7u- (1(R) hydroxy1-methylbutyl)-6,l4-endo-ethenotetrahydronororipavine, (-)2' hydroxy 2methyl 6,7- benzomorphan, noracylmethadol, phenoperidine, a-dlmethadol,fi-dl-methadol, a-l-methadol, B-dl-acetylmethadol, a-l-acetylmethadoland fi-l-acetylmethadol, in oral dosage form and containing for eachanalgetic dose of the analgetic dose of the analgetic agent an amount ofnaloxone sufficient upon parenteral administration of said dosage formto negate the analgetic and euphoric action of the composition.

A still further preferred embodiment is an orally effective, analgeticcomposition which, upon parenteral administration, does not produceanalgesia, euphoria or physical dependence, said composition comprisingby weight one part of naloxone per 40 to 400 parts of meperidine, 0.4 to4 parts of oxymorphone, 13 to 130 parts of alphaprodine, 12 to 120 partsof anileridine, 2 to 20 parts of dextromoramide, 12 to 120 parts ofdextropropoxyphene, 2.5 to 25 parts of methadone, 0.3 to 3 parts ofmetopon, 0.8 to 8 parts of levorphanol, 0.8 to 8 parts of phenazocine,60 to 600 parts of etoheptazine, 20 to 200 parts of propiram, 8 to 80parts of profadol, 40 to 400 parts of phenampromide, to 100 parts ofthiambutene, 8 to 80 parts of pentazocine, 4 to 40 parts of pholcodeine,to 150 parts of codeine, 2 to parts of oxycodone, 2.5 to parts ofdihydrocodeinone, 0.8 to 8 parts of hydromorphone, 0.1 to 1 partsfentanyl, 15 to 150 parts 3 trans dimethylamino 4phenyl-4-trans-carbethoxy- A'-cyclohexene, 6 to 60 parts of3-dimethylamino-O-(4- methoxyphenylcarbamoyl)-propiophenone oxime, 5 to50 parts of (-);8 2' hydroxy-2,9-dimethyl-5-phenyl-6,7- benzomorphan, 13to 130 parts of (-)2-hydroxy-2-(3- methyl 2 butenyl) 9methyl-5-phenyl-6,7-benzomorphan, 5 to 50 parts of pirinitramide, 5 to50 parts of (-)(X 5,9 diethyl 2'-hydroxy-2-methyl-6,7-benzomorphan, 5 to50 parts of ethyl 1-(2-dimethylaminoethyl)- 4,5,6,7 tetrahydro 3 methyl4 oxo 6 phenylindole2-carboxylate, 20 to 200 parts of l-benzoylmethyl-2,3-dimethyl-3-(m-hydroxyphenyl)-piperidine, 0.1 to 1 parts of N-allyl7a (1-(R)-hydroxy-1-methylbutyl)-6,l4-endo-ethenotetrahydronorporipavine, 14 to parts of (-)2' hydroxy 2methyl 6,7 benzomorphan, 5 to 50 parts of noracylmethadol, 2 to 20 partsof phenoperidine, 2.5 to 25 parts of a-dl-methadol, 40 to 400 parts ofB-dl-methadol, 0.3 to 3 parts of a-l-methadol, 0.8 to 8 parts offl-dl-acetylmethadol, 0.8 to 8 parts of a-l-acetylmethadol or 0.4 to 4parts of p-l-acetylmethadol, in oral dosage form.

An embodiment of the present invention is an orally effective, analgeticcomposition which, upon parenteral administration, does not produceanalgesia, euphoria or physical dependence, said composition comprisingabout 0.1 mg. to about 10 mg. of naloxone per analgetic oral dose of anorally active, strong analgetic in oral unit dosage form.

A preferred embodiment of the present invention is an orally effective,analgetic composition which, upon parenteral administration, does notproduce analgesia, euphoria or physical dependence comprising about 0.1mg. to about 2.5 mg. of naloxone per analgetic oral dose of an orallyactive, strong analgetic in oral dosage form.

Another preferred embodiment is an orally effective, analgeticcomposition which upon parenteral administration produces neitheranalgesia nor euphoria, said composition comprising about 0.1 mg. toabout 2.5 mg. of naloxone per arialgetic oral dose of an analgeticselected from the group comprising meperidine, oxymorphone,alphaprodine, anileridine, dextromoramide, dextropropoxyphene,methadone, metopon, levorphanol, phenazocine, etoheptazine, propiram,profadol, phenampromide, thiambutene, pentazocine, pholcodeine, codeine,oxycodone, dihydrocodeinone, hydromorphone, fentanyl, 3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy A cyclohexene,3-dimethylamino O (4-methoxyphenylcarbamoyl) -propiophenone oxime,3-2'-hydroxy-2,9-dimethyl 5 phenyl-6,7-benzomorphan, -)2'-hydroxy-2-(3-methyl 2 butenyl) 9 methyl-5-phenyl-6,7-benzomorphan, pirinitramide,a-5,9-diethyl-2'-hydroxy-2- methyl-6,7-benzomorphan, ethyl1-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro 3methyl-4-oxo-6-phenylindole- Z-carboxylate, l-benzoylmethyl 2,3dimethyl3-(m-hydroxyphenyl)-piperidine, N-allyl-7a(1 (R)-hydroxy-1-methylbutyl)-6,14 endo ethenotetrahydronororipavine, ()2'-hydroxy 2methyl-6,7-benzomorphan, noracylmethadol, phenoperidine, a-dl-methadol,fl-dl-methadol, a-l-methadol, ,B-dl-acetylmethadol, a-l-acetylmethadoland fi-l-acetylmethadol, in unit oral dosage form.

A preferred embodiment of the present invention is the method ofproducing analgesia in mammals which comprises the oral administrationof an orally effective, analgetic composition which, upon parenteraladministration, does not produce analgesia, euphoria or physical.dependence, said composition comprising an orally in effective butparenterally effective dose of naloxone and. an orally active, stronganalgetic in oral dosage form.

A preferred embodiment of the present invention is the method ofproducing analgesia in mammals which comprises the oral administrationof an orally effective, analgetic composition which, upon parenteraladministration, does not produce analgesia, euphoria or physicaldependence, said composition comprising an orally ineffective butparenterally effective dose of naloxone and an analgetic dose of anorally active, strong analgetic in oral dosage form.

Another preferred embodiment is the method of producing analgesia inmammals which comprises the oral administration of an orally effective,analgetic composition which, upon parenteral administration, does notproduce analgesia, euphoria or physical dependence, said compositioncomprising naloxone and an orally active, strong analgetic in oraldosage form and containing for each analgetic dose of the analgeticagent an amount of naloxone sufficient upon parenteral administration ofsaid oral dosage form to negate the analgetic, euphoric and physicaldependence producing action of the composition.

A more preferred embodiment is the method of producing analgesia in manwhich comprises the oral administration of an orally effective,analgetic composition which, upon parenteral administration, does notproduce analgesia, euphoria or physical dependence, said compositioncomprising naloxone and an analgetic selected from the group consistingof meperidine, oxymorphone, alphaprodine, anileridine, dextromoramide,dextropropoxyphene, methadone, metapon, levorphanol, phenazocine,etoheptazine, propiram, profadol, phenampromide, thiambutene,pentazocine, pholcodeine, codeine, oxycodone, dihydrocodeinone,hydromorphone, fentanyl, 3-trans-dimethylamino 4phenyl-4-trans-carbethoxy-A'-cyclohexene, I i-dimethylamino O(4-rnethoxyphenylcarbamoyl)- propiophenone oxime,,6-2'-hydroxy2,9-dimethyl-5- phenyl-6,7-benzomrphan, ()2'-hydroxy 2(3-methyl-2-butenyl) 9 methyl 5 phenyl-6,7-benzomorphan, pirinitramide,()oz 5,9-diethyl-2'-hydroxy 2 methyl- 6,7-benzomorphan, ethylI-(Z-dimethylaminoethyl)-4,5,6, 7-tetrahydro-3-methyl-4-oxo-6phenylindole 2 carboxylate, l-benzoylmethyl 2,3 dimethyl 3(m-hydroxyphenyl)-piperidine, N-allyl-7a-(1(R)-hydroxy 1methylbutyl)-6,14 endo ethenotetrahydronororipavine, 2'-hydroxy 2methyl-6,7-benzomorphan, noracylmethadol, phenoperidine, u-dl-methadol,13-dl-methadol, a-lmethadol, ,B-dl-acetylmethadol, u-l-acetylmethadoland fl-l-acetylmethadol, in oral dosage form and containing for eachanalgetic dose of the analgetic agent an amount of naloxone suflicientupon parenteral administration of said dosage form to negate theanalgetic and euphoric action of the composition.

A still further preferred embodiment is the method of producinganalgesia in man which comprises the oral administration of an analgeticdose of an orally eifective, analgetic composition which, uponparenteral administration, does not produce analgesis, euphoria orphysical dependence, said composition comprising by weight one part ofnaloxone per 40 to 400 parts of meperidine, 0.4 to 4 parts ofoxymorphone, 13 to 130 parts of alphaprodine, 12 to 120 parts ofanileridine, 2 to 20 parts of dextromoramide, 12 to 120 parts ofdextropropoxyphene, 2.5 to 25 parts of methadone, 0.3 to 3 parts ofmetopon, 0.8 to 8 parts of levorphanol, 0.8 to 8 parts of phenazocine,60 to 600 parts of etoheptazine, 20 to 200 parts of propiram, 8 to 80parts of profadol, 40 to 400 parts of phenampromide, 10 to 100 parts ofthiambutene, 8 to 80 parts of pentazocine, 4 to 40 parts of pholcodeine,to 150 parts of codeine, 2 to parts of oxycodone, 2.5 to parts ofdihydrocodeinone, 0.8 to '8 parts of hydromorphone, 0.1 to 1 partfentauyl, 15 to 150 parts 3-transdimethylamino-4-phenyl-4-transcarbethoxy-A'-cyclohexene, 6 to 60 parts of3-dimethylarnino-O-(4-methoxyphenylcarbamoyl)-propiophenone oxime, 5 to50 parts of (.-)fl-2-hydroxy-2,9-dimethyl 5 phenyl-6,7-benzomorphan, 13to 130 parts of ()2-hydroxy-2-(3-methyl-2-butenyl)-9-methyl-5-phenyl-6,7-benzomorphan, 5 to 50 parts ofpirinitramide, 5 to 50 parts of (-)a-5,9-diethyl-2-hydroxy-2-methyl-6,7-benzomorphan, 5 to 50 parts of ethyl 1(Z-dimethylaminoethyl) 4,5,6,7 tetrahydro-3-methyl-4-oxo-6-phenylindole-2-carboxylate, 20 to 200 parts of1-benzoylmethyl-2,3-dimethyl-3-(m-hydroxyphenyl)-piperidine, 0.1 to 1part of N-allyl-7u-( l-(R)-hydroxy- 1-methy1butyl)-6,14-endoethenotetrahydronororipavine, 14 to 140 parts of(-)2-hydroxy-2-methyl-6,7-benzomorphan, 5 to 50 parts ofnoracylmethadol, 2 to 20 parts of phenoperidine, 2.5 to 25 parts ofot-dl-methadol, 40 to 400 parts of ,B-dbmethado], 0.3 to 3 parts ofa-l-methadol, 0.8 to 8 parts of fi-dl-acetylmethadol, 0.8 to 8 parts ofa-l-acetylmethadol or 0.4 to 4 parts of fi-l-acetylmethadol, in oraldosage form.

An embodiment is the method of producing analgesia in man whichcomprises the oral administration of an orally effective, analgeticcomposition which, upon parenteral administration, does not produceanalgesia, euphoria or physical dependence, said composition comprisingabout 0.1 mg. to about 10 mg. of naloxone per analgetic oral dose of anorally active, strong analgetic in oral unit dosage form.

A preferred embodiment is the method of producing analgesia in man whichcomprises the oral administration of an orally effective analgeticcomposition which, upon parenteral administration, does not produceanalgesia, euphoria or physical dependence, said composition comprisingabout 0.1 mg. to about 2.5 mg. of naloxone per analgetic oral dose of anorally active, strong analgetic in oral unit dosage form.

A most preferred embodiment is the method of producing analgesia in manwhich comprises the oral administration of an orally efl'ective,analgetic composition which, upon parenteral administration, does notproduce analgesia, euphoria or physical dependence, said compositioncomprising about 0.1 mg. to about 2.5 mg. of naloxone per analgetic oraldose of an analgetic selected from the group comprising meperidine,oxymorphone, alphaprodine, anileridine, dextromoramide,dextropropoxyphene, methadone, metopon, levorphanol, phenazocine,etoheptazine, propiram, profadol, phenampromide, thiambutene,pentazocine, pholcodeine, codeine, oxycodone, dihydrocodeinone,hydromorphone, fentanyl, 3 trans dimethylamino 4 phenyl 4trans-carbethoxy-A'-cyclohexene, 3-dimethylamino 0(4-methoxyphenylcarbamoyl) propiophenone oxime, ()fi-2'-hydroxy 2,9dimethyl-5-phenyl-6,7-benzomorphan, 2'-hydroxy 2 (3methyl-Z-butenyl)-9-methyl-5-phenyl 6,7 benzomorphan, pirinitramide,(-)a-5,9-diethyl- 2' hydroxy 2 methyl-6,7-benzomorphan, ethyl 1-(2-dimethylaminoethyl)-4,5,6,7 tetrahydro 3 methyl-4- oxo 6 phenylindole 2carboxylate, l-benzoylmethyl- 2,3-dimethyl 3 (mhydroxyphenyl)-piperidine, N- allyl-7a-(1-(R)-hydroxy 1 methylbutyl)6,l4-endoethenotetrahydronororipavine, ()2 hydroxy-Z-methyl-6,7benzomorphan, noracylmethadol, phenoperidine, a-dl-methadol,fl-dl-methadol, a-l-methadol, B-dl-acetylmethadol, a-l-acetylmethadoland fl-l-acetylmethadol, in unit oral dosage form.

The weight ratios of naloxone to the analgetic agents in the compositionof the instant invention have been determined either from the literatureor in our laboratories. It has been found that the parenteraladministration of one part by weight of naloxone will efficiently andreliably negate (counteract) the parenteral etfect of up to about 400parts of meperidine, 4 parts of oxymorphone, 130 parts of alphaprodine,120 parts of anileridine, 20 parts of dextromoramide, 120 parts ofdextropropoxyphene, 25 parts of methadone, 3 parts of metopon, 8 partsof levorphanol, 8 parts of phenazocine, 600 parts of etoheptazine, 200parts of propiram, parts of profadol, 400 parts of phenampromide, partsof thiambutene, 80 parts of pentazocine, 40 parts of pholcodeine, 150parts of codeine, 20 parts of oxycodone, 25 parts'of dihydrocodeinone, 8parts of hydromorphone, 1 part of fentanyl, 150 parts of3-trans-dimethylamino-4-phenyl-4- trans-carbethoxy-A'-cyclohexene, 60parts of 3-dimethylamino-O-(4 methoxyphenylcarbamoyl)-propiophenoneoxime, 50 parts of 18-2'-hydroxy 2,9 dimethyl-5- phenyl 6,7benzomorphan, parts of (-)2'-hydroxy 2 (3 methyl 2butenyl)-9-methyl-5-phenyl- 6,7 benzomorphan, 50 parts of pirinitramide,50 parts of ()a-5,9 diethyl 2' hydroxy 2methyl-6,7-benzomorphan, 50parts of ethyl 1-(2 dimethylaminoethyD- 4,5,6,7 tetrahydro 3methyl-4-oxo-6-phenylindole-2- carboxylate, 200-parts of1-benzoylmethyl-2,3-dimethy1- y1-6,7-benzomorphan, 50 parts ofnoracyhnethadol, 20

parts of phenoperidine, 25 parts of a-dl-methadol, 400 parts offi-dl-methadol, 3 parts of a-1-methadol, 8 parts offl-dl-acetylmethadol, 8 parts of a-l-acetylmethadol or 4 parts offl-l-acetylmethadol.

It has also been established that naloxone can be administered orally ina quantity up to about ten times the minimal parenteral dose required toabolish parenteral activity of the analgetic without abolishing the oralactivity of the analgetic, e.g., 1 part naloxone per 40 partsmeperidine, 1 part naloxone per 0.8 part phenazocine, etc.

Working from these parenteral ratios which define the minimum efiicientand reliable parenteral dose of naloxone required to negate theparenteral dose of the analgetic agent, other experiments have beenconducted to determine the largest practical and economical quantity ofnaloxone that can be administered orally per oral therapeutic dose ofthe analgetic agent without abolishing the oral eifect of the analgeticagent. It was found that the one can safely administer naloxone orallyin a quantity up to about times the minimal parenteral dose necessary toabolish parenteral activity of the orally effective dose of theanalgetic. It is emphasized here that it is frequently possible toorally administer more than 10 times the minimum parenteral dose of thenaloxone without abolishing the oral analgetic effect.

The rat tail-flick method was used in our laboratory to determine thenaloxone analgetic ratios of some of the euphoretic analgetic agents.The method adopted for use is that originally described by DAmour andSmith (J. Pharmacol. Exper. Therap. 72:74, 1941) in which a heat lamp isfocused onto a rats tail and the elapsed time between onset of the lightand a flick of the tail is measured. The method consists of holding theanimal either by wrapping it in a towel or box with the tail laying in aV-shaped groove. The light and timer are connected in series with aswitch so that both the light and timer can be turned on and olfsimultaneously. When the rat quiets down, the light and timer are turnedon and the operator watches for the response, which is a characteristicflick of the tail. The response, in the control period for the untreatedrat is usually about 3.5 seconds. Rats weighing between 160 and 190grams have been found most uniform in response in the control andtreated trials.

An example of one experiment is the determination of the parenteralratio for oxymorphone in rats.

Untreated rats produced the desired tail-flick in 3.5 seconds. Adiffering amount of oxymorphone hydrochloride was administeredsubcutaneously to a sequence of rats to determine the minimum quantityof oxymorphone hydrochloride necessary to delay the tail flick till 7seconds. The amount required was 0.22 mg./kg. body weight.

A series of rats so treated with oxymorphone hydrochloride were thenchallenged with varying doses of subcutaneously administered naloxonehydrochloride to determlne the minimum quantity of naloxone that wouldcompletely negate the analgesia produced by the oxymorphone. Thequantity required was 0.025 mg./kg. body weight. The parenteralnaloxone/analgetic ratio is therefore approximately 1 part naloxonehydrochloride to about 9 parts of oxymorphone hydrochloride.

Once it was established that the parenteral administration of 1 part ofnaloxone would completely negate the analgetic activity of about 9 partsof oxymorphone, it was necessary to determine how the ratio would workwhen the combination was administered orally.

A series of starved rats were orally dosed by stomach tube with varyingquantities of oxymorphone to determine the oral dose of oxymorphonenecessary to produce a tail-flic response of 7 seconds. The dose ofoxymorphone hydrochloride was dissolved in 20 ml. of water per kg. ofbody weight. It was determined that 50 mg./ kg. orally produced thedesired tail-flick response in 6 of 6 rats. A dose of 25 mg./kg.produced the desired response in 5 of 6 rats.

A composition of 1.1 grams of naloxone hydrochloride and oxymorphonehydrochloride was prepared containing 0.1 gram of naloxone HCl and 1.0gram of oxymorphone HCl (1:10 ratio).

A dose of 27.5 rug/kg. of body weight of the above composition dissolvedin 20 ml. of water was administered by stomach tube. Six of 6 ratsshowed a tail-flick" response of at least 7 seconds. When a dose of 55mg./ kg. was administered, 6 of 6 rats again showed the desiredanalgetic effect of at least 7 seconds.

In a similar experiment to that described above, it was determined that50 mg./kg. of phenazocine orally produced the desired tail-flickresponse in 5 of 6 rats. A dose of mg./kg. produced the desired responsein 6 of 6 rats.

A composition of 0.64 gm. of naloxone hydrochloride and phenazocinehydrobromide was prepared containing 0.04 gm. of naloxone HCl and 0.60gm. of phenazocine HBr (1:15 ratio).

A dose of 53.3 mg./kg. of body weight of the above composition dissolvedin 20 ml. of water was administered by stomach tube. Six of 6 ratsshowed a tail-flick" response of at least 7 seconds. When a dose of106.6 mg./kg. was administered, 6 of 6 rats again showed the desiredanalgetic effect of at least 7 seconds.

In further experiments with phenazocine HBr, it was found thatcompositions containing doses of naloxone in 100% excess of the minimalantagonistic parenteral dose still produced analgesia upon oraladministration.

The conclusion can therefore be drawn that a parenterally antagonisticdose of naloxone can be administered orally without interfering with theanalgetic efiect of the orally administered analgetic.

Applicants acknowledge the possibility of dilferent naloxone/analgeticratios due to species dilferences, e.g., rats versus man, etc. Forexample, our laboratory studies show 1 part or parenterally administerednaloxone hydrochloride will negate the analgetic effect of about 9 partsof parenterally administered oxymorphone hydrochloride in the rat.However, it is reported in the literature that 1 part of naloxone HClparenterally is required to negate the analgetic effect of 4 parts ofoxymorphone HCl parenterally in man.

Likewise, it was found that 1 part naloxone parenterally would negatethe effect of about 15 parts of phenazocine HBr in the rat, but theliterature reports that 1 part of naloxone parenterally is required tonegate the eifect of 8 parts of phenazocine HBr parenterally in man.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 Gram Naloxonehydrochloride 0.10

Methadone hydrochloride L 0,500 Lactose qs. ad. 100 capsules.

Corn starch Talc a a qs. ad. 100 capsules.

11 Example 4 Naloxone hydrochloride 0.5 Methadone hydrochloride 5.0Lactosc qs. ad. 100 capsules.

Example 5 Naloxone hydrochloride 0.4 Codeine sulfate 30 Magnesiumstearate qs. 'Corn starch qs. ad. 1000 tablets.

- Example 6 'Naloxone hydrochloride 1.0 Dextropropoxyphene hydrochloride65.0 Lactose, qs. ar. 1000 capsules.

Example 7 Naloxone (or a salt thereof) .050

Camphorated opium tincture, U.S.P., qs. ad. 100 ml.

We claim:

1. A method for the treatment of drug-addicted subjects which comprisesoral administration of an effective amount of a composition consistingessentially of (a) methadone in an amount suflicient to substantiallyprevent narcotic craving and(b) naloxone in an amount sufficient toinduce withdrawal symptoms when said composition is administeredparenterally but insuflicient to negate the action of said methadonewhen the composition is administered orally.

2. The method of claim 1 wherein the weight ratio of methadone tonaloxone is from about 2.5:1 to about 25:1.

3. The method of claim 1 wherein said composition comprise from about0.1 to about 2.5 milligrams of naloxone per analgetic oral dose ofmethadone.

References Cited UNITED STATES PATENTS OTHER REFERENCES Merck Index, 8thed., 1968, p. 371.

Goodman et al.: Pharmacological Basis of Therapeutics, 3rd ed., 1965,pp. 274-278.

ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Assistant Examiner U.S.Cl. X.R. 42410, 330

